GI Cancer Armamentarium Gains Traction With Immunotherapy, Targeted Agents

Jimmy Hwang, MD

The FDA approvals of pembrolizumab (Keytruda) and nivolumab (Opdivo), as well as fam-trastuzumab deruxtecan-nxki [Enhertu], in gastric and gastroesophageal junction (GEJ) cancer represent significant advances in the treatment of patients with gastrointestinal (GI) malignancies, explained Jimmy Hwang, MD, who added that expectations for ongoing research and development are equally as bright.

“The take-home message is a positive one and one of excitement and energy in an area that has been neglected. There’s room for hope, and there’s room for motion. We’ve seen it, and I expect that we’ll continue to see it,” said Hwang, an oncologist at Levine Cancer Institute of Atrium Health, in an interview with OncLive® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies.

The virtual meeting covered systemic therapies in gastric cancer and metastatic pancreatic cancer, the surgical management of pancreatic cancer, hepatobiliary surgery, and treatment sequencing in hepatocellular carcinoma (HCC).

In the interview, Hwang, who chaired the event, discussed the frontline indications for checkpoint inhibitors in gastric cancer and their effect on subsequent treatment decisions, the growth of targeted therapy across GI cancers, and expectations for future research and development.

OncLive®: Will most patients with gastric and GEJ cancer receive a checkpoint inhibitor in the up-front setting now that pembrolizumab and nivolumab have frontline indications?

Hwang: Now, I expect that most patients will get a checkpoint inhibitor as part of their initial treatment in the metastatic setting, which will have downstream implications. One of the challenges is that the FDA was very broad in their approvals of pembrolizumab and nivolumab in these diseases. It’s statistically justifiable, but it also is a little bit challenging, especially when we think of ourselves as a taxpayer. For the payers in general, what’s left out of many of these evaluations is: Do the costs justify the benefits of such a broad approval when some of the data suggest that some populations may benefit more than others?

Do you have a preference with regard to which regimen you use in practice?

It’s not an easy question to answer, because there’s a lot of nuances that play into that. I wouldn’t say that there is a particular regimen that stands out over the others, realistically, although the data are a little bit different among the [regimens]. One would say, platinum fluoropyrimidine, although in our practice, most of those patients get oxaliplatin with either 5-flourouracil or capecitabine, so a FOLFOX- or a CAPOX-type regimen. However, that’s not necessarily universally true. That’s not what all the studies used, but from a practical standpoint, that’s what we have been using at our institution as our chemotherapy baseline.

We have just added nivolumab most easily from a data standpoint, but I believe most people think pembrolizumab is similarly efficacious, but that’s a little bit of an extrapolation. One of the questions is whether every patient should be getting these agents, which is the way the FDA approved them, at least for esophageal cancer.

Or should there be some patients who have a particular CPS [combined positive score] who should be the ones who are getting [these checkpoint inhibitors]? That part is still a bit fuzzy. According to the FDA approvals, anybody can get them, but when you look at the studies, there did appear to be more of a benefit for the patients who had a higher CPS. Those are some things that we’re going to need to try to weed out, including from a patient-benefit standpoint, but also, from a cost standpoint. I don’t necessarily envision every country having the same broad approval given the data that have been presented. I’ll be curious to see how that plays out going forward.

How do frontline treatment decisions affect a patient’s options in the second-line setting?

[Treatment in] the second-line setting depends on what happens the first-line setting. If you’ve used a checkpoint inhibitor in the first-line setting, is there still benefit in the second-line setting to continue it the same way that we’ve seen in HER2-positive breast cancer. This is with trastuzumab [Herceptin] where you continue trastuzumab beyond progression, and what we see in colorectal cancer with bevacizumab [Avastin] where you use in the first-line setting and the second-line setting? Is that applicable in gastroesophageal cancer? We don’t know what happens when the patient has disease progression on first-line therapy that includes a checkpoint inhibitor. We are struggling with that in HCC [hepatocellular carcinoma] as my colleague, Dr. Laura Musselwhite, talked about in her presentation. Where do we go in that second-line setting?

The reality is now we’re dealing with a completely data-free zone from that standpoint. There is a little bit more evidence but not necessarily a ton when you look at HER2-amplified gastric and esophageal adenocarcinoma where trastuzumab deruxtecan has recently been approved for treatment in those patients. If a patient has HER2 [amplification] and they’ve gotten pembrolizumab with chemotherapy and trastuzumab in the first-line setting, would you use trastuzumab deruxtecan in the second-line setting? You can, but there are no data on what happens after pembrolizumab. However, at least it’s approved in that second-line setting.

Apart from trastuzumab deruxtecan, what other targeted agents have garnered interest?

There’s bemarituzumab, the FGFR2-directed antibody, which was presented at the 2021 Gastrointestinal Cancers Symposium and certainly had promising data, which led to a phase 3 study. The Claudin inhibitor is another agent under ongoing study. There are additional targeted therapies that are being investigated, but it remains to be seen what will happen for patients with homologous recombination deficiency, [where we are] looking at either PARP inhibitors or ATR inhibitors in those settings. We are all hopeful that they will bring benefit.

Now, each of these [targets] end up representing relatively small slices of the overall population, but those slices add up, and eventually, hopefully, we’ll end up comprising the entire pie. But we’re still in that development process. That’s one of the exciting things about working in these times, is that you can see the advances that have gone on even within the span of the past decade and a half.

Switching over to some of the other talks in the program, there was a presentation on pancreatic cancer highlighted that the NAPOLI 3 (NCT04083235) trial. How might that study affect the treatment paradigm if it yields positive results?

Everybody is looking forward to seeing the results of that trial. That [study] really is one of the only ways that we’re going to be able to see whether NALIRIFOX is better than gemcitabine plus nano albumin-bound paclitaxel. There are strands of evidence to suggest that FOLFIRINOX is better, but there are strands to suggest that it may not be better. NAPOLI 3 may give us some evidence in this direction if it’s positive.

Now, if it’s negative, the question will come up of: Does that mean that FOLFIRINOX is not better than gemcitabine and nab-paclitaxel [Abraxane]? Or, does it have something to do with the NAPOLI 3 combination, specifically? Did there end up being enough of a compromise in the ability to deliver the irinotecan aspects of things, or the platinum or the fluoropyrimidine because of myelosuppression? If it’s a positive study, it will answer some questions. Although, it won’t answer the nanoliposomal irinotecan vs irinotecan question.

Moving on to another lecture from the program, we heard a little bit about the CELESTIAL study (NCT01908426) in HCC. How has that study contributed to the use of cabozantinib (Cabometyx) in patients with pretreated HCC?

The CELESTIAL study gives us an additional option. CELESTIAL was a little bit of a broader study than regorafenib [Stivarga] was in the sense that it investigated [cabozantinib in the] second- and third-line settings. From those standpoints, it was beneficial to have that [agent]. There were questions that [the study] couldn’t answer by its design, however. Is [cabozantinib] better than, worse than, or about the same as regorafenib? I don’t know. Is the mechanism the same or different? There are theoretical differences between cabozantinib and regorafenib and cabozantinib and sorafenib [Nexavar], but they’re theoretical. We don’t know if there are practical differences on that front. However, having said that, [cabozantinib] was beneficial in the patients treated.

The toxicity profile certainly looked, broadly speaking, somewhat better than regorafenib, acknowledging that you’re evaluating different populations. Perhaps you shouldn’t be making too many broad conclusions from that standpoint. But, again, certainly, [the study] gives us additional options, and because [cabozantinib] was studied in the second- and third-line setting, it gives us a little more flexibility as well.

Reflecting on each presentation, what is your expectation for the future landscape?

I look at [these presentations], and what I see is excitement. Maybe a little bit less so with regards to pancreatic cancer because we’re still waiting [on advances]. On the other hand, there are irons in the fire. There has been progress, there have been advances for patients with metastatic gastroesophageal cancer. There are advances for patients with resected esophageal cancer. Dr. Musselwhite’s talk sort of built on where we will go from here with regard to HCC; there are promising avenues for exploration.

This is a set of diseases that, when you look at the worldwide numbers, are among the top seven leading causes of cancer-related mortality. We finally see that there’s starting to be progress with immunotherapy with regards to gastroesophageal cancer and HCC. Even with traditional chemotherapies, we see the potential for benefits, we see the potential for motion for patients with locoregional pancreatic cancer.